Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
  • A61K9/7061—Polyacrylates

Definitions

• This invention relates to a pressure-sensitive adhesive sheet material containing estradiol in the adhesive portion of the sheet material.
• This invention further relates to a method of treating conditions associated with estradiol deficiency, such as osteoporosis and headaches, nausea, depression, hot flashes or other discomforts that often occur during menopause.
• Estradiol is a natural estrogen which has limited oral effectiveness because it is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. In contrast, the skin metabolizes estradiol only to a small extent. Therefore, transdermal administration produces therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conjugates, and requires smaller total doses than does oral therapy. Since estradiol has a short half-life (about one hour), transdermal administration of estradiol allows a rapid decline in blood levels after a transdermal system is removed.
• Estraderm R is an estradiol transdermal system available from CIBA Pharmaceutical Company. This system comprises four layers: a transparent polyester film; a drug reservoir of estradiol and alcohol gel with hydroxypropyl cellulose; an ethylene-vinylacetate copolymer membrane; and an adhesive formulation of light mineral oil and polyisobutylene for adhering the patch to skin.
• Japanese Application 57075917 describes the manufacture of a tacky tape for use with a variety of sex hormones including valeric acid-estradiol .
• the tape is prepared by (1) copolymerizing (a) 60-98 parts by weight of dodecyl methacrylate, (b) 2-40 pts. wt. of a functional monomer and (c) 0-40 pts. wt. of at least one short chain unsaturated monomer selected from vinyl acetate, an alkyl acrylate, and an alkyl methacrylate; (2) combining the drug with the copolymer; and (3) spreading the resulting composition onto base material.
• U. S. Patent 3,598,123 describes a medical bandage for use with a variety of drugs including estradiol.
• the bandage comprises: a backing member and a layer of pressure-sensitive adhesive containing a plurality of discrete microcap ⁇ ules containing the drug. Acrylic adhesives are specifically mentioned.
• U.S. Patent No. 4,460,372 describes a transdermal device comprising a backing and an adhesive layer, the adhesive layer containing both estradiol and a microencapsulated percutaneous absorption enhancer such as ethanol.
• GB Application 2158355 describes an estradiol containing transdermal dosage form comprising: a solid non-polymeric gel; a mixture of propylene glycol and glycerin; the therapeutic agent dispersed in the solvent mixture; and a thin, flexible, non-polymeric matrix in planar form.
• the mixture of propylene glycol and glycerine is described as enhancing the skin penetration of the therapeutic agent.
• U.S. Patent Nos. 3,598,122, 4,379,452, 4,573,996, 4,585,454, 4,624,665, and 4,460,372 all describe estradiol transdermal patches which include layers in addition to a backing and an adhesive layer.
• estradiol transdermal patches which include layers in addition to a backing and an adhesive layer.
• many of these patents describe patches comprising a backing, a drug reservoir layer; a semipermeable membrane; and an adhesive layer coated on the exterior surface of the semipermeable membrane.
• Said U.S. Patent No. 4,573,996 discloses a variety of penetration enhancers in Col. 11, lines 44-68.
• European Application 86.902978.5 describes a transdermal nitroglycerin delivery system comprising a flexible backing and a pressure-sensitive adhesive coating comprising an acrylic polymer and nitroglycerin.
• the adhesive coating may also comprise a skin penetration enhancing combination comprising a fatty acid ester of a fatty acid and glyceryl monolaurate.
• U.S. Patent No. 4,722,941 discloses transdermal and oral formulations employing a fatty acid of medium chain length and optionally a monoglyceride of a saturated or unsaturated fatty acid of about 6 to 18 carbon atoms to enhance drug absorption.
• the formulations may include a steroid.
• Glyceryl monolaurate, isopropyl myri ⁇ tate and ethyl oleate are known enhancers for transdermal administration of medicaments.
• the present invention provides a novel adhesive-coated sheet material comprising: a) a flexible backing; and b) a pressure-sensitive adhesive-coating contiguousl adhered to one surface of said backing and comprising a homogeneous mixture of: i) an acrylic polymer comprising at least about 91 t 98 percent by weight of a hydrophobic monomeric acrylic or ethacrylic acid ester of an alkyl alcohol based on the weight of all monomers in th polymer, the alkyl alcohol containing 4 to 10 carbon atoms; ii) estradiol in an amount by weight of about 0.2 to percent of the total weight of the adhesive coating; and iii) a skin penetration enhancer combination comprisin isopropyl myristate and glyceryl monolaurate in amounts of about 5 to 20 percent and about 1 to 6 percent by weight, respectively, based on the weight of the adhesive-coating with the relative amounts being selected so as to enhance the penetration of the estradiol through skin as compared to when the
• the present invention also provides a novel adhesive-coated sheet material comprising: a) a flexible backing; and b) a pressure-sensitive adhesive-coating contiguousl adhered to one surface of said backing and comprising a homogeneous mixture of: i) an acrylic copolymer comprising (1) about 60 to 8 percent by weight of a hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol based on the weight of all of the monomer in the copolymer, the alkyl alcohol containing 4
• estradiol in an amount by weight of about 0.2 to percent of the total weight of the adhesive coating; and iii) a skin penetration enhancer combination comprisin isopropyl myristate and glyceryl monolaurate in amounts of about 5 to 20 percent and about 1 to 6 percent by weight, respectively, based on the weight of the adhesive coating, with the relativ amounts being selected so as to enhance the penetration of the estradiol through skin as compared to when the adhesive coating is free of the skin penetration enhancers; the sheet material being suitable for substantially continuous transdermal delivery of estradiol to a subject over a prolonged period in an amount which is therapeutic
• the skin penetration enhancer combination further contains ethyl oleate.
• the drawing is an isometric view of a diffusion cell f measuring flux of estradiol across mammalian skin.
• the present invention relates to pressure-sensitive adhesive sheet materials comprising a backing and a layer o pressure-sensitive adhesive containing estradiol coated thereon. Further, this invention relates to a method of treating conditions associated with estradiol deficiency.
• treating a condition associated with estradiol deficiency is meant administering a dose of estradiol in an amount and at a rate which eliminates or reduces the occurrence of one or more of the following conditions: osteoporosis, headaches, nausea, depression, hot flashes and any other discomfort that occurs during menopause.
• prolonged period as used in the instant specification and claims is meant for a period of at least 12 hours.
• the adhesive ⁇ utilized in the practice of the inventio should be substantially chemically inert to estradiol.
• Suitable acrylic adhesive polymers for use in one embodimen of the invention comprise in an amount of about 91 to 98 percent by weight, and preferably about 94 to 98 percent by weight, respectively, of all monomers in the polymer of a hydrophobic monomeric acrylic or methacrylic acid ester of alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms.
• suitable monomers are those discussed below in connection with the "A Monomer”.
• These adhesive polymers further comprise minor amounts of other monomers such as the "B Monomers” listed below.
• Preferred adhesives are acrylic pressure-sensitive adhesive copolymer ⁇ comprising A and B monomers as follows:
• Monomer A is a hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol, the alkyl alcohol containin 4 to 10 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 6 to 8 carbon atoms, and most preferably 8 carbo atoms.
• suitable A monomers are n-butyl, n-pent n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloct i ⁇ ooctyl and 2-ethylhexyl acrylate ⁇ .
• the mo ⁇ t preferred A monomer i ⁇ i ⁇ ooctyl acrylate.
• Monomer B i ⁇ a reinforcing monomer ⁇ elected from the group con ⁇ isting of acrylic acid; methacrylic acid; alkyl acrylates and methacrylates containing 1 to 3 carbon atoms the alkyl group; acrylamide; methacrylamide; lower alkyl-sub ⁇ tituted acrylamide ⁇ (i.e.
• the preferred B monomers are acrylic acid, methacrylic acid, the above-described alkyl acrylate ⁇ and methacrylates, acrylamide, methacrylamide, and the above-described lower alkyl substituted acrylamide ⁇ .
• the mo preferred B monomer is acrylamide.
• the acrylic copolymer compri ⁇ e ⁇ about 60 to 80 percent by weight (and preferably about 70 to 80 percent by weight) of the above-mentioned hydrophobic monomeric acrylic or methacryli acid ester of an alkyl alcohol based on the weight of the monomers in the copolymer; about 4 to 9 percent by weight based on the weight of all monomers in the copolymer of a reinforcing monomer selected from the group consisting of acrylic acid, methacrylic acid, an alkyl acrylate or methacrylate containing 1 to 3 carbon atoms in the alkyl group, acrylamide, methacrylamide, a lower alkyl-sub ⁇ titute acrylamide, diacetone acrylamide and N-vinyl-2-pyrrolidone; and about 15 to 35 percent by weight (and preferably about to 25 percent by weight) of vinyl acetate based on the weig of all monomers in the copolymer.
• a reinforcing monomer selected from the group consisting of
• the preferred acrylic or methacrylic acid ester is isooctyl acrylate and the preferred reinforcing monomer i ⁇ acrylamid U ⁇ e of vinyl acetate in preparing the acrylic polymer i ⁇ a convenient way to reduce the amount of re ⁇ idual monomer in the final preparation a ⁇ ha ⁇ been de ⁇ cribed in U.S. Patent No. 4,737,577.
• adhe ⁇ ive copolymer ⁇ of the above type are known an their method of preparation is well known to those skilled i the art, having been de ⁇ cribed for example, in U.S. Patent 24,906 of Ulrich, incorporated herein by reference. Since t pres ⁇ ure- ⁇ en ⁇ itive adhe ⁇ ive ⁇ de ⁇ cribed above are inherently rubbery and tacky and are ⁇ uitably heat and light ⁇ table, there i ⁇ no need to add tackifier ⁇ or ⁇ tabilizer ⁇ . However, ⁇ uch may be added if de ⁇ ired.
• estradiol i ⁇ present in the adhe ⁇ ive in a pharmaceutically effective amount Generally thi ⁇ amount wil be from about 0.2 to 12 percent by weight of the total weigh of the pre ⁇ sure-sen ⁇ itive adhesive layer of the sheet material, and will preferably be about 1 to 5 percent by weight. The most preferred is an amount of about 2 to 3.5 percent by weight. It has been found that the addition of certain skin penetration enhancers significantly enhances the penetratio of estradiol in vitro when this phenomena i ⁇ measured using the hairless mouse ⁇ kin model as de ⁇ cribed hereinbelow.
• the adhe ⁇ ive sheet material of the invention ha ⁇ an adhesive coating comprising a combination of two or more ingredients in an amount effective to enhance the penetrati of estradiol through skin a ⁇ compared to when said adhe ⁇ ive coating i ⁇ free of the ⁇ kin penetration enhancers.
• the adhesive-coating comprise ⁇ i ⁇ opropyl myri ⁇ tate and glyceryl monolaurate a ⁇ penetration enhancer ⁇ .
• the adhesive-coating additionally comprise ⁇ ethyl oleate.
• the i ⁇ opropyl myristate will generally be present in a amount of about 5 to 20 percent by weight, and preferably about 5 to 15 percent by weight, of the total weight of the adhe ⁇ ive coating and the glyceryl monolaurate will generall be pre ⁇ ent in an amount of about 1 to 6 percent, and preferably about 2 to 4 percent by weight.
• the adhe ⁇ ive-coating additionally contain ⁇ ethyl oleate
• ethyl oleate will generally be pre ⁇ ent in an amount by weight of about 4 to 18 percent, and preferably about 5 to 15 percent ba ⁇ ed on the weight of the adhe ⁇ ive coating.
• ethyl oleate i ⁇ present the total weight of ethyl oleate and isopropyl myristate will not exceed about 25 percent by weight of the adhe ⁇ ive-coating.
• the backing of the tape may be occlu ⁇ ive, non-occlu ⁇ ive or breathable film.
• the backing may be any of the normal material ⁇ for pre ⁇ ure- ⁇ en ⁇ itive adhesive tapes such as polyethylene, particularly low-density polyethylene, linear low den ⁇ ity polyethylene, high den ⁇ ity polyethylene, randomly-oriented nylon fiber ⁇ , polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon and like.
• the backing ⁇ hould be ⁇ ub ⁇ tantially non-reactive wi estradiol.
• the presently preferred backing i ⁇ low den ⁇ ity polyethylene.
• Low den ⁇ ity polyethylene backing ⁇ provide a excellent barrier to lo ⁇ of e ⁇ tradiol when u ⁇ ed with the adhe ⁇ ive formulation ⁇ of the invention, including tho ⁇ e formulation ⁇ which contain a skin penetration enhancer.
• Backing ⁇ which are layered ⁇ uch as polyethylene- aluminum-polyethylene composites are al ⁇ o ⁇ uitable.
• the mouse or human ⁇ kin (20) i ⁇ mounted epidermal ⁇ ide up between the upper and lower portion ⁇ of the cell ( and (22), which are held together by mean ⁇ of a ball joint clamp (23).
• the cell below the ⁇ kin is filled with 30% N-methyl-2-pyrrolidone in water to act a ⁇ the "acceptor" fluid.
• the acceptor fluid i ⁇ ⁇ tirred u ⁇ ing a magnetic ⁇ tirring bar (24) and a magnetic ⁇ tirrer (not illu ⁇ trated) .
• the ⁇ ampling port (25) i ⁇ ⁇ toppered except when in u ⁇ e.
• a known amount of a formulation to be evaluated i ⁇ applied to the epidermal (upper) ⁇ ide of the ⁇ kin in a uniform layer a ⁇ follows: The desired area and weight of a sheet material formulation is accurately determined so tha the amount of adhesive applied to the cell can be accurate determined. The sheet material i ⁇ applied to the skin alre mounted on the diffu ⁇ ion cell and pre ⁇ sed to cause uniform contact to the skin.
• the cell is then placed in a constant temperature (31 33 C) constant humidity chamber (generally maintained at humidity between 40 and 50%, preferably about 50%) and kep there throughout the experiment.
• the chamber utilizes a heat exchanger coupled to a constant temperature bath, wit fan to circulate air.
• a saturated calcium nitrate solution u ⁇ ed to maintain the humidity.
• the acceptor fluid i ⁇ ⁇ tirr by means of a magnetic stirring bar throughout the experim to as ⁇ ure a uniform sample and a reduced diffusion layer o the dermal side of the ⁇ kin.
• the acceptor fluid i ⁇ removed specified time intervals and fresh fluid is immediately ad to replace the withdrawn fluid.
• the withdrawn aliquots are analyzed for drug content by conventional high pre ⁇ ure liquid chromatograpy and the cumulative amount of the drug penetrating the ⁇ kin i ⁇ calculated.
• Plot ⁇ of the cumulativ drug penetration a ⁇ a function of time give a profile of t drug flux mea ⁇ ured in microg/cm /hour.
• the u ⁇ e of other ⁇ kin ⁇ uch a ⁇ human ⁇ kin in the above apparatu ⁇ has confirmed the utility of the formulations of the invention.
• the sheet materials of the present invention are preferably prepared by combining dry adhesive, estradiol a the ⁇ kin penetration enhancers with an organic solvent.
• Preferred organic solvent ⁇ are methanol and ethyl acetate.
• the total solids content will be in the range of about 15 40% and preferably about 20 to 35%.
• the re ⁇ ulting mixture shaken at a high ⁇ peed until a homogeneous solution is obtained and then allowed to ⁇ tand to di ⁇ ipate air bubble
• the re ⁇ ulting formulation may be wet ca ⁇ t or coated by wet-cast or knife coating techniques to provide a predetermined uniform thickne ⁇ of the wet adhe ⁇ ive formulation onto a ⁇ uitable relea ⁇ e liner. Thi ⁇ ⁇ heet i ⁇ t dried and laminated onto a backing material using conventional method ⁇ .
• Suitable release liners are known ⁇ ilicone-type relea ⁇ e liner ⁇ ⁇ uch as that available under trade de ⁇ ignation Daubert 164, from Daubert Co. which are coated onto polye ⁇ ter film.
• the adhe ⁇ ive coated ⁇ heet material of the invention may be in the form of a tape, a patch, a ⁇ heet, a dres ⁇ ing or other forms known to the art will be apparent to one skilled in the art.
• the adhesive coated ⁇ heet material will contain about 0.2 to 7. mg, and preferably about 1.0 to 2.0 mg, of e ⁇ tradiol per 5 cm of the ⁇ heet material.
• the sheet material will generally be about 1 to 40 cm 2 , and preferably 10 to 30 cm 2 in dimension.
• a transdermal patch of the invention will b applied to the ⁇ kin of a mammal (preferably a human) and wi be replaced with a fre ⁇ h patch a ⁇ required to maintain the therapeutic effect.
• Those ⁇ killed in the art may ea ⁇ ily determine the frequency at which the patche ⁇ of the inventi ⁇ hould be replaced to achieve the de ⁇ ired therapeutic effect.
• Flux rates are expressed in units of micrograms of e ⁇ tradio per cm 2 for the time period ⁇ pecified in the example. Each re ⁇ ult repre ⁇ ent ⁇ the average value of several (e.g., 3 to independent determination ⁇ .
• the adhesive-coated laminate was dried first a 180° F for 3 minutes and then at 240° for 3 minutes. The dried adhesive coating was then stripped off the release liner and placed into a small glass bottle. The foregoing procedure results in a reduction of the amount of residual monomer which may be contained in the adhesive copolymer.
• Example 1 A mixture of 200.62 g of 95:5 isoctyl acrylate:acrylamide adhesive copolymer, 33.75 g of isopropy myristate, 8.75 g of glyceryl monolaurate, 6.88 g of e ⁇ tradiol USP, 525.00 g of ethyl acetate and 58.33 g of methanol wa ⁇ placed in a jar. The jar was placed on a platform shaker and shaken for about 18 hours. The formulation was allowed to ⁇ tand until all the air bubble ⁇ had dissipated. The formulation was coated at a thicknes ⁇ 0.022 inches onto a ⁇ ilicone coated 5 mil liner.
• the laminate was oven dried for 2 minutes at 125°F, for 2 minut at 185°F and for 2 minutes at 235°F (too vigorous condition for drying may result in loss of a major amount of the isopropyl myristate).
• the resulting adhesive coating contained 80.25 percent 95:5 i ⁇ ooctyl acrylate:acrylamide adhesive copolymer, 13.50 percent isopropyl myristrate, 3.5 percent glyceryl monolaurate and 2.75 percent e ⁇ tradiol.
• T material was allowed to cool and was then laminated onto th corona treated surface of a 3 mil low density polyethylene backing. The laminate was die cut into 2 cm 2 patches.
• Penetration through hairless mouse skin was measured using the diffusion apparatus and method described above.
• the acceptor fluid was 30% N-methyl-2-pyrrolidone in water. Three independent determinations were carried out. The average penetration in 24 hours was 74 micrograms/cm .
• Example ⁇ 2-4 Using the general method of Example 1 the formulations shown in Table 1 were prepared and the penetration through hairles ⁇ mou ⁇ e skin measured.
• the acceptor fluid wa ⁇ 30% N-methyl-2-pyrrolidone in water. Patche ⁇ which mea ⁇ ured 2 cm were employed. Table 1
• Example 5 A mixture of 23.31 g of isooctyl acrylate:acrylamide:vinyl acetate adhesive copolymer,
• the resulting adhesive coating contained 75.5 percent 75:5:20 isooctyl acrylate:acrylamide:vinyl acetate adhesive copolymer, 2.75 percent estradiol, 12.0 percent isopropyl myristate, 6.2 percent ethyl oleate and 3.6 percent glyceryl monolaurate.
• the material was then laminated onto the corona treated surface of a 3 mil low density polyethylene film and die cut into 5.07 cm 2 patches. Penetration through hairless mouse skin was measured. The acceptor fluid was 30% N-methyl-2-pyrrolidone in water. Three independent determinations were made. The average amount penetrating in 24 hours was 84 microgra s/cm 2 .
• Examples 6-8 Using the general method of Example 5 the formulations shown in Table 2 were prepared and the penetration through hairless mouse skin measured.
• the adhesive used was an isooctyl acrylate:acrylamide:vinyl acetate 75:5:20 copolymer.
• the acceptor fluid was 30% N-methyl-2-pyrrolidone in water. Patches measuring 5.07 cm 2 were employed.
• estradiol 14.0% isopropyl myristate

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• Health & Medical Sciences (AREA)
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• Epidemiology (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
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• Steroid Compounds (AREA)
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• Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)

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Citations (7)

• 1989
  • 1989-02-27 EP EP89903563A patent/EP0402407B1/en not_active Expired - Lifetime
  • 1989-02-27 JP JP1503327A patent/JP2931002B2/ja not_active Expired - Lifetime
  • 1989-02-27 WO PCT/US1989/000786 patent/WO1989007951A1/en active IP Right Grant
  • 1989-02-27 AT AT89903563T patent/ATE109357T1/de not_active IP Right Cessation
  • 1989-02-27 DE DE68917292T patent/DE68917292T2/de not_active Expired - Lifetime
  • 1989-02-27 AU AU32809/89A patent/AU630347B2/en not_active Expired
  • 1989-03-29 CA CA000594966A patent/CA1338819C/en not_active Expired - Lifetime
• 1992
  • 1992-08-13 AU AU20978/92A patent/AU651234B2/en not_active Expired
• 1996
  • 1996-12-05 LU LU88849C patent/LU88849I2/fr unknown
• 1997
  • 1997-02-14 NL NL970007C patent/NL970007I1/nl unknown

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